INTRODUCTION:

Many important biochemical compounds and drugs of natural origin contain heterocyclic ring structures. The presence of heterocyclic rings in such diverse type of compounds is strongly indicative of profound effects of such molecule to exert on physiological activity and recognition of this is reflected abundantly in efforts to find useful synthetic drugs.

Also many heterocyclic compounds due to their specific activity are employed in the treatment of many infectious diseases. Their use in the treatment is attributed to their inherent toxicity to various pathogens.

Though the heterocyclic compounds were recognized lately, their biological activities attracted the researches. Intensive research in diverse heterocyclic derivatives continues to yield new medicinal agents. One such area is that of Thiazole.

Thiazole¹ was first described by Hantzsch and weber in 1887. Popp confirmed its structure in 1889. The thiazole ring has been extensively studied and it forms a part of vitamin B, penicillins and the antibacterial thiazoles. Reduced thiazoles serve in the study of polypeptides and proteins and occur as structural units in compounds of biological importance.

The partially reduced thiazole is known as Thiazoline^2,
3 and completely reduced Thiazole or tetrahydro derivative of Thiazole is known as Thiazolidine⁴.

The oxa derivative of Thiazolidine is known as thiazolidinone. Thiazolidinones are five membered heterocyclic compounds with one nitrogen atom and one sulphur atom. Depending upon the position of oxo group they are named as 2-Thiazolidinone, 4-Thiazolidinone and 5-Thiazolidinone. They were reported to possess one or other biological activities⁷.

4-Thiazolidinone plays vital role owing to its wide range of therapeutical, pharmaceutical and industrial importance. 4-thiazolidinones gained attraction by researchers due to their biological activities.

4-Thiazolidinones play a vital role owing to their wide range of physiological, biological and pharmacological activities. Several substituted thiazolidinones have been found to possess Anaesthetic, Anti-convulsant, Anti-tubercular and sedative properties²¹.

4-Thiazolidinones are well known compounds that were found to possess various biological activities like Anti-bacterial²⁹, Anti-fungal³⁰, Anti-viral, Anti-tubercular³¹, Anthelmentic³⁵, Insecticidal, Ameobicidal and Anti-aids properties.It was also found that they possess Analgesic, Anti-inflammatory³⁶, Anti-thyroid¹⁰, Anti-convulsant and Anti-parkinsonism activities.

Biological activities like CNS stimulatory, Anaesthetic, Hypnotic, sedative, Local anaesthetic²¹ are found to be associated with compounds having 4-thiazolidinone moiety.

A wide spectrum of biological activities are found to be associated with compounds having 4-thiazolidinone moiety.This may result in the formation of some interesting bioactive compounds. Keeping this in view the synthesis of Aryl oxy-4-thiazolidinones have been carried out.

MATERIAL AND METHODS:

The melting points of compounds were determined by open tube capillary using Thermonik precision apparatus in Celsius scale and uncorrected. IR spectra were recorded using KBr pellets on PERKIN ELMER 8201 PC IR spectrophotometer, 1H NMR spectra of the final compound were recorded on BRUKER DRX 300 NMR spectrometer (300MHz). All spectra were obtained in a mixture of CDCL3 and TFA (Tri-fluro acetic acid).Mass spectra (FAB-MS) were recorded on 70V on Jeol D-300 spectrophotometer (Jeol Ltd., Tokyo, Japan).

GENERAL PROCEDURE:

In the present dissertation Substituted Aryloxy-4-Thiazolidinones have been synthesized. The synthesis consists of four steps which are as follows:

1. Preparation of Aryl oxy ethyl acetate:

Mixture of phenol (0.2 mol), ethyl chloro acetate ( 0.2 mol ) and anhydrous potassium carbonate ( 0.2 mol ) was taken in a round bottom flask containing 300 ml of acetone and refluxed on a water bath for 16 hours. Excess of acetone was removed from the reaction mixture and the contents were cooled to room temperature and poured into ice cold water with constant stirring. The oily layer was extracted with ether in a separating funnel. Ether layer was collected and the excess of ether was removed. The ether so obtained was purified by distillation under reduced pressure.

2. Preparation of Aryl oxyacet hydrazide:

Aryl oxyethyl acetate (0.2 mol) and hydrazine hydrate (0.2 mol) was taken in a round bottom flask containing 250 ml of ethanol. The mixture was refluxed on a water bath for 4 hours, after excess of ethanol was removed from the reaction mixture by distillation and cooled to room temperature and poured into ice-cold water. The solid separated was collected by filteration and dried. Further purification was done by recrystalisation from ethanol.

3. Preparation of Schiff bases:

Aryl oxyacet hydrazide (0.2 mol) and approximately substituted aldehyde (0.2 mol) were dissolved in a minimum quantity of ethanol and the mixture was taken in a round bottom flask. To this mixture 2 or 3 drops of conc sulphuric acid was added and this mixture is refluxed on a water bath for 10 hrs. After refluxing, the excess of ethanol was removed from the reaction mixture and cooled it to room temperature. Then it was poured into ice cold water and filtered. The solid obtained was collected and recrystalized from ethanol.

4. Preparation of 2-(substituted phenyl)-3-substituted phenoxy-acetamido-4-thiazolidinone:

Schiff base (0.2 mol) and thioglycolic acid (0.22 mol) and benzene (200 ml) were taken in a Strak and Dien apparatus. The mixture was refluxed on a water bath for 12 hrs, after refluxing; the excess of benzene was removed by evaporation. The contents were cooled to room temperature and poured into ice cold water and filtered. The solid so obtained was collected and purified by recrystalisation from ethanol.

Anti-fungal activity :

Each Petri dish containing Sabourauds agar medium was inoculated with one bacterial culture by spreading the suspension of the culture with a sterile cotton swab. Each petridish was divided into 4 equal portions along the diameter. Each portion was used to place one disc. Two discs of each sample were placed on two portions, two discs were placed one with griseofulvin and another impregnated with the solvent, Dimethylformamide (DMF).

All petridishes were kept in the refrigerator for 30 minutes to allow the diffusion of the sample into the surrounding agar medium. Then the plates were incubated at 25°C for 48 hours and results were noted. Diameter of the zones of inhibition were produced were measured and the average diameter for each sample was calculated and the results are given in table. The diameters were compared with that produced by the standard antibiotic.

Diameter of the disc: 6mm.

Amount of the test compound: 50µ/disc.

Standard drug: Griseofulvin (25µ/disc.)

Control (Solvent): Dimethylformamide.

Table: 1 Anti-fungal activity of the synthesized compounds:

Sl. No	Compound No.	Diameter of zone of inhibition
Sl. No	Compound No.	Candida albicans	Aspergillus niger
1.	1-S1	9	7
2.	1-S2	12	13
3	1-S3	9	17
4	2-S1	7	8
5	2-S2	8	6
6	2-S3	12	7
7	3-S1	7	9
8	3-S2	11	12
9	3-S3	10	13
10	Griseofulvin	14	15
11	DMF	-	-

Zone of inhibition was measured in mm.

Table: 2. Names of the synthesized Aryloxy-4-Thiazolidinones:

1S-1: 2-(o-hydroxy phenyl)-3-phenoxy-acetamido-4-thiazolidinone.

1S-2: 2-(4¹-hydroxy-3¹-methoxy phenyl)-3-phenoxy-acetamido-4-thiazolidinone.

1S-3: 2-(3¹,4¹-dimethoxy phenyl)-3-phenoxy-acetamido-4-thiazolidinone.

2S-1: 2-(o-hydroxy-phenyl)-3-(p-Chloro-phenoxy)-acetamido-4-thiazolidinone

2S-2: 2-( 4¹-hydroxy-3¹-methoxy phenyl)-3-(p-chloro phenoxy-acetamido)-4-thiazolidinone.

2S-3: 2-(3^1,4¹-dimethoxy-phenyl-3-(p-chloro phenoxy-acetamido)-4-thiazolidinone.

3S-1: 2-(o-hydroxy-phenyl)-3-(p-Cresyloxy-acetamido)-4-thiazolidinone.

3S-2: 2-(4¹-hydroxy-3¹-methoxy-phenyl)-3-(p-cresyloxy-acetamido-4-thiazolidinone

3S-3: 2-(3¹,4¹-dimethoxy-phenyl)-3-(p-cresyloxy-acetamido)-4-thiazolidinone.

Table: 3 Anthelmintic activity studies of synthesized compounds:

Sl No.	Compound No.	Conc. of the Compound (mg)	Mean paralyzing Time ( min)# S.E	Mean death time (Min)# S.E
1	Control	-	N.E	N.E
2	Piperzine	200	30.66 ± 1.18	52.02 ± 1.5
3	1-S1	200	32.66 ± 1.22	54.42 ± 1.1
4	1-S2	200	36.38 ± 54	58.42 ± 1.26
5	1-S3	200	32.34 ± 28	50.46 ± 1.20
6	2-S1	200	32.32 ± 1.22	52.68 ± 2.18
7	2-S2	200	34.42 ± 2.24	52.32 ± 1.14
8	2-S3	200	30.46 ± 1.16	50.22 ± 2.28
9	3-S1	200	34.26 ± 0.24	54.56 ± 1.16
10	3-S2	200	32.56 ± 0.28	50.56 ± 1.20
11	3-S3	200	33.26 ± 0.24	52.56 ± 1.16

Table: 4. Physical data of the compounds: 1S-1 to 3S-3.

Name of the compound	Molecular formula	Molecular Wt	Melting point	% yield
1S-1	C17 H16N2SO4	344	196 C	56 %
1S-2	C18 H19N2SO4	374	212 C	54 %
1S-3	C19 H22N2SO4	368	220 C	57 %
2S-1	C17 H15N2O5 S Cl	378	201 C	58 %
2S-2	C18 H19N2O5 S Cl	408	217 C	63 %
2S-3	C19 H19N2O5 S Cl	422	226 C	67 %
3S-1	C18H18N2O4 S	359	205 C	61 %
3S-2	C19H20N2O5 S	389	234 C	59 %
3S-3	C20H22N2O5 S	403	227 C	64 %

Table: 5. Spectral data of the compound 1S-1 and 2S-2:

Compound: 1S-1

IR Spectra: A peak at 1705.9 cm-1 may be due to thiazolidinone C=O stretching. The peak due to amido C=O is at 1682.59 cm-1. The peak due to C=C stretching is seen at 1594.84 cm-1 and a peak 3096.15 cm-1 is due to C-H stretching. A peak at 639.43 cm-1 is seen due to C-S-C and a peak at1269.90 cm-1 may be due to C-O-C stretching.

NMR Spectra: δ 3.4 (1H,-N-CH), δ 3.7(2H, -S-CH2), δ 4.8 (2H, -O-CH2), δ 6.9-7.8(9H, Ar-H), δ 8.6 (1H, -NH-N).

MASS Spectra: In the mass spectrum recorded, the molecular ion peak was observed at m\e 344 corresponding to the molecular formula C17H18N2O4S.

Compound: 2S-2

IR Spectra: A peak at 1710.21 cm^-1may be due to thiazolidinone C=O stretching. A peak at 1677.77 cm^-1 due to amido C=O is seen. The peak due to C=C stretching is seen at 1618.95 cm^-1 and a peak at 3066.26 cm^-1 is may be due to C-H stretching. A peak at 689.43 cm^-1 is may be due to C-S-C and a peak at1298.82 cm^-1 may be due to C-O-C stretching.

NMR Spectra: δ 3.4 (1H, -N-CH), δ 3.7-(2H,-S-CH2), δ 4.6 (2H, -O-CH2), δ 6.8-7.5(8H, Ar-H), δ 8.4- (N-NH).

MASS Spectra: In the mass spectrum recorded the molecular ion peak was observed at m\e 408 corresponding to the molecular formula C18Hs17N2ClO5S and chlorine isotope peak was observed at m\z 410.

Another set of 5 earthworms was kept as control in 50 ml suspension of distilled water and 0.5% tween 80.

50 ml each of the suspensions of the test compounds were added into separate Petri plates containing 5 earthworms in each. The time required for the paralysis and death of the worms were noted. The death time was ascertained by placing the earth worms in water bath at 50º C, which stimulated the movement if worm was alive.

CONCLUSION:

A Series of Aryloxy-4-Thiazolidinones were designed on the basis of Literature review on various thiazolidinones. The entire synthesized thiazolidinone derivative remitted in product with good yield purity of all the synthesized compounds were checked by their melting point. All the synthesized compounds have shown antifungal activity and anthelmintic activity. On tested organisms in comparison to standard drug against griseofulvin and piperzine. As we consider all results obtained from anti-fungal activity and anthelmintic activity, tests together we can say that the entire compounds tested are active towards micro-organisms.

From the anti-fungal activity, it is evident that the synthesized compounds show moderate to good activity. Among the tested compounds in the series; compounds (1S-1, 3S-2, 3S-3) shown good activity against Candida albicans and Aspergillus niger. Compounds (1S-3, 2S-3 ) shown moderate activity.

Evaluation of the anthelmintic activity for Aryloxy-4-thiazolidinone derivatives was carried out. All the compounds were found to possess anthelmintic activity. Compound 2-S3 showed better activity than the standard drug.

ACKNOWLEDGEMENTS:

The authors are thankful to Indian Institute of science for their valuable help in the fast processing of spectral data and also express heartly gratitude and thankful to our esteemed guide and teacher Dr. prof. D.Satyanarayana,M.pharm,phD,F.I.C., principal, NGSM institute of pharmaceutical sciences, Mangalore for his guidance, valuable suggestions and constant encouragement throughout the period and providing all the facilities required for the work.

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Received on 03.12.2009 Modified on 29.01.2010

Asian J. Research Chem. 3(2): April- June 2010; Page 508-512